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@PHDTHESIS{Averbek:245675,
      author       = {Averbek, Sera},
      title        = {{E}ffects of {O}-{G}lc{NA}cylation on radiation-induced
                      {DNA} double-strand break repair},
      school       = {Technical University of Darmstadt},
      type         = {Dissertation},
      address      = {Darmstadt},
      reportid     = {GSI-2022-00018},
      pages        = {70 P.},
      year         = {2021},
      note         = {Strat. Univ.: TU Darmstadt DFG GRK 1657. Published under CC
                      BY-SA 4.0 International; Dissertation, Technical University
                      of Darmstadt, 2021},
      abstract     = {DNA integrity is continuously threatened by various hazards
                      such as cytotoxic chemicals, radiation or metabolic
                      reactions, which potentially inflict DNA damage including
                      DNA double-strand breaks (DSBs), the most harmful type of
                      DNA damage. To maintain genome integrity, damaged DNA must
                      be repaired accurately to prevent genomic instability that
                      leads to diseases including cancer. Post translational
                      modifications (PTMs) such as phosphorylation, ubiquitination
                      or acetylation are essential to orchestrate DNA
                      damage-response and repair mechanisms. Recent studies
                      revealed an involvement of
                      O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in DNA
                      damage response, which is an abundant, dynamic and
                      reversible PTM of cellular proteins and very sensitive to
                      environmental nutrient supply. O-GlcNAcylation occurs at
                      amino acid Ser or Thr residues, which are also a target of
                      phosphorylation. Therefore, O-GlcNAcylation and
                      phosphorylation are suggested to compete. The aim of the
                      study was to investigate different aspects of the regulatory
                      role of O-GlcNAcylation on DNA-damage response in dependence
                      of damage complexity and cell-cycle phase. O-GlcNAc
                      transferase (OGT) and O-GlcNAcase (OGA) inhibitors were used
                      in order to change cellular O-GlcNAcylation level. DNA
                      damage of different complexity was induced with low (X-rays)
                      or high LET (linear energy transfer) radiation (C-, Fe- and
                      He-ion) in selected human cell lines. Different approaches
                      were used including γH2AX-foci assay, live-cell microscopy,
                      Fluorescence Lifetime Microscopy (FLIM), westernblot
                      analysis and protein-immunoprecipitation to detect DSB
                      rejoining, accumulation of NBS1 at DNA damage site,
                      chromatin states and O-GlcNAcylation of repair relevant
                      factors upon irradiation respectively. First, induction of
                      O-GlcNAcylation at the DSB site was examined with
                      fluorescence co-localization analysis of 53BP1 and O-GlcNAc.
                      They showed a radiation induced increase of O-GlcNAcylation
                      within the nuclear compartment after X-ray or heavy-ion
                      irradiation; specific O-GlcNAcylation at DSB sites however,
                      was observed after heavy-ion irradiation only. The influence
                      of O-GlcNAcylation on DSB repair was examined after X-ray
                      and charged particles irradiation. It revealed that
                      O-GlcNAcylation promotes DSB repair independent of
                      DNA-damage complexity. Promotion of DSB repair occurs by
                      stimulating homologous recombination (HR) and potentially an
                      additional repair mechanism, which was revealed by studying
                      repair of radiation induced DSBs in dependence of an
                      siRNA-mediated knockdown of HR factor RAD51 together with
                      modulating O-GlcNAcylation. Live-cell experiments suggested
                      that inhibition of OGT disturbs the accumulation of NBS1 to
                      X-ray induced DSBs. Moreover, MDC1 was confirmed to be
                      O-GlcNAcylated, and HR factors CtIP and BRCA1 were shown to
                      be modulated by O-GlcNAcylation upon irradiation. OGT and
                      OGA activity also regulate chromatin compaction states that
                      are proposed to be an important determinant of DSB repair
                      pathway choice. Collectively, the data demonstrated multiple
                      roles of O-GlcNAcylation in the repair of radiation induced
                      DSBs concluding that O-GlcNAcylation is an important PTM to
                      maintain genomic stability.},
      cin          = {BIO},
      cid          = {I:(DE-Ds200)BIO-20160831OR354},
      pnm          = {633 - Life Sciences – Building Blocks of Life: Structure
                      and Function (POF4-633) / 02NUK054A - Verbundprojekt
                      VERCHROMT II: Erkennung, Verarbeitung und biologische
                      Konsequenzen von Chromatinschäden nach Teilchenbestrahlung
                      II, Teilprojekt A (BMBF-02NUK054A) / FAIR Phase-0 - FAIR
                      Phase-0 Research Program (GSI-FAIR-Phase-0)},
      pid          = {G:(DE-HGF)POF4-633 / G:(DE-Ds200)BMBF-02NUK054A /
                      G:(Ds200)GSI-FAIR-Phase-0},
      experiment   = {$EXP:(DE-Ds200)SBio_Jakob-20200803$ /
                      $EXP:(DE-Ds200)UBio_Jakob_X0-20200803$},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:tuda-tuprints-201923},
      doi          = {10.26083/TUPRINTS-00020192},
      url          = {https://repository.gsi.de/record/245675},
}